Multiple sclerosis (MS) is a debilitating central nervous system (CNS) disease that has features of autoimmunity. It has been reported that brain lesions of MS contain reactive microglia that express the immune response antigen, Ia. Ia antigens in this disease as well as in most other autoimmunities are generally thought to serve a conventional role in stimulating T cells. More recently we have begun to use the twitcher mouse as a model to study Ia in another demyelinating disease. Twitcher is a genetically-inherited demyelinating model caused by a defect in the galactosyl-ceramidase gene which results in defective galactosyl-ceramide breakdown. With time, oligodendrocytes become dysfunctional resulting in subsequent demyelination. The onset of severe demyelination is coincidental with the hyperexpression of Ia in the brains of these mice, yet T cells are not prominent in the brains of severely afflicted animals. This provides an excellent animal model to elucidate the function of CNS Ia that may be distinct from its conventional role as a T cell stimulating molecule. To directly examine the role of CNS Ia hyperexpression in the twitcher disease, we have produced Ia negative, twitcher transgenic mice. These mice lack Ia expression and also have the defective galactosyl-ceramidase gene. Our results show that the lack of Ia expression resulted in decreased neuropathology, significantly lower numbers of microglia in the CNS, and decreased twitching compared to Ia-positive counterparts. Together these results suggest that Ia is an exacerbating factor in this demyelinating model. The goals of this proposal are: (l) To determine the role of CNS Ia in other demyelinating as well as nondemyelinating neurodegenerative disease models. (2) To better define the role of T cells in the twitcher mice either by the use of reagents to deplete T cells or by the use of CD4-knockout mice. (3) To determine if Ia serves as a signalling molecule that activates brain microglia to synthesize cytokines that may be detrimental to oligodendrocytes. (4) To examine the effects of immunotherapeutic agents known to downregulate class II MHC expression on disease progression in the twitcher mice. These studies are pertinent to the Program Announcement because they will provide: (l) new demyelinating models to study the role of CNS Ia hyperexpression, (2) information on the interactions of activated glial cells and oligodendrocytes, and (3) the rationale for and the testing of specific immunotherapies that may alleviate demyelination.